Author contributions: Badiani RG, Becker V, Lemos LB and Matos CAL collected all the human material and performed the research; Andrade LEC, Dellavance A and Lanzoni VP provided reagents and analytical tools and were also involved in editing the manuscript; Badiani RG, Perez RM, Silva AEB and Ferraz MLG designed the study, analyzed the data and wrote the manuscript.

RESULTS: Among patients with hepatitis C and intense interface hepatitis there was a low prevalence of autoantibodies (ANA = 12%, SMA = 5%, LKM-1 = 0%) and the median γ-globulin level was within the normal range. Typical histological findings of autoimmune disease were observed in only two cases (2%). After applying the score for diagnosis of autoimmune hepatitis, only one patient was classified with a definitive diagnosis of autoimmune hepatitis. Since overlap with autoimmune hepatitis was not the explanation for the intense necroinflammatory activity in patients with chronic hepatitis C we sought to identify the variables associated with this finding. The presence of intense interface hepatitis was associated with more advanced age, both at the time of infection and at the time of the biopsy, and higher prevalence of blood transfusion and alcohol abuse.

CONCLUSION: Although possible, overlap with autoimmune hepatitis is a very rare association in HCV-infected patients with intense interface hepatitis, an unusual presentation which seems to be related to other host variables.

Hepatitis C is the main cause of liver-related morbidity and mortality and represents a worldwide public health problem[1]. An estimated 170 million individuals are infected with hepatitis C virus (HCV), corresponding to 3% of the world population[2].

Infection with HCV is characterized by a high chronicity rate (70% to 85%)[3-6], progression to cirrhosis in 20% to 30% of cases[1,6-8] and the development of hepatocarcinoma in 5% of patients[9]. In addition, this infection represents the most common indication for liver transplantation worldwide[10].

Histological analysis of patients chronically infected with HCV usually reveals some degree of fibrosis, generally associated with the presence of mild or moderate necroinflammatory activity[11]. However, a histological pattern demonstrating intense interface hepatitis has been reported[12,13]. In these cases a possible association with autoimmune hepatitis has been suggested, raising doubts regarding the correct diagnosis and the establishment of adequate treatment[14-16]. The objective of the present study was to evaluate the overlap with autoimmune hepatitis in HCV-infected patients with intense interface hepatitis.

MATERIALS AND METHODS

Patients

Patients chronically infected with HCV followed up at the Federal University of Sao Paulo between 1993 and 2006, who were submitted to a liver biopsy, were studied. The inclusion criteria were chronic infection with HCV (characterized by HCV-RNA positivity) and the presence of intense interface hepatitis upon histological analysis. Patients previously treated or who were HBsAg-positive were excluded.

A control group consisting of patients chronically infected with HCV, who presented absent, mild or moderate interface hepatitis, was included in order to evaluate if an eventual association of autoimmune hepatitis with hepatitis C was restricted to patients with intense necroinflammatory activity. In the absence of such association, a comparison with the control group was performed to evaluate other factors possibly related to intense interface hepatitis. This control group was randomly selected from the database of the Hepatitis Outpatient Clinic of the Federal University of Sao Paulo (1:1 ratio). The same exclusion criteria were adopted for the control group. For the comparative analysis, patients with associated diseases [human immunodeficiency virus (HIV), end-stage renal disease and kidney transplant] were excluded from both groups.

The study was approved by the local Ethical Committee.

Epidemiological characteristics

The patients were evaluated regarding gender, age, estimated duration of infection, age at the time of infection, abusive alcohol consumption (men > 40 g/d and women > 20 g/d), the presence of parenteral risk factors (intravenous drug use, hemodialysis or blood transfusion before 1992) and associated diseases (HIV, end-stage renal disease and kidney transplant). This information was recovered from charts where the data were systematically evaluated with a standardized questionnaire. The duration of infection was evaluated in patients with parenteral risk factors and was estimated from the first year of intravenous drug use or hemodialysis or from the year of first transfusion in patients who had received blood transfusions before 1992.

Laboratory tests

The liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT) and alkaline phosphatase were assayed by an automated kinetic method and were expressed as the following index: value obtained/upper limit of normal. γ-globulins were assayed by electrophoretic fractionation on agarose gel and densitometry. All biochemical tests were performed within a period of 3 mo from the date of the liver biopsy.

Antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-liver/kidney microsomal antibody (anti-LKM) and anti-mitochondrial antibody were determined by indirect immunofluorescence and the titer was considered significant when higher than 1/40.

A liver biopsy was indicated in all patients, irrespective of ALT levels. Liver tissue fragments were obtained by percutaneous biopsy with a Tru-cut® needle. The liver biopsy slides were stained with hematoxylin-eosin, Masson’s trichrome, Prussian blue (Perls’ stain), and silver for reticular fibers (Gomori’s stain), and were reviewed by a single pathologist who was unaware of the clinical data. Histological analysis included the determination of the grade of interface hepatitis and of the stage of fibrosis, which were assessed using a semiquantitative scoring system according to Ludwig[17]. Patients were classified as having intense interface hepatitis if they presented a score of periportal activity = 4, in a scale varying from 0 (no inflammation) to 4 (intense necroinflammatory activity).

In order to better characterize the presence of eventual histological components suggestive of autoimmune injury, the presence of plasma cell infiltrate and rosettes was also analyzed.

Scoring system for diagnosis of autoimmune hepatitis

All patients were evaluated regarding the reviewed international diagnostic criteria for autoimmune hepatitis according to the International Autoimmune Hepatitis Group[18].

Statistical analysis

The χ2 test and Fisher’s exact test were used for statistical analysis of categorical variables. Numerical variables were compared between the two groups using the Student t-test and Mann-Whitney test. A level of significance of 0.05 (α = 5%) was adopted.

RESULTS

Among the 1759 patients chronically infected with HCV submitted to a liver biopsy during the study period, 92 presented intense interface hepatitis, corresponding to 5.2% of the initial sample. The characteristics of these patients are shown in Table 1. (General characteristics of patients with intense interface hepatitis n (%))

Among patients presenting intense interface hepatitis, there was a low prevalence of autoantibodies and the median γ-globulin level was within the normal range. Typical histological findings of autoimmune disease were observed in only two cases (2%). After applying the scoring system for diagnosis of autoimmune hepatitis only one patient was classified as having a definitive diagnosis.

Since overlap with autoimmune hepatitis was not the explanation for the intense necroinflammatory activity in patients with chronic hepatitis C, we sought to identify the variables associated with this finding. Therefore, we compared epidemiological, laboratory and histological characteristics between patients with intense interface hepatitis and a randomly selected control group consisting of chronic HCV-infected patients with absent, mild or moderate interface hepatitis. For comparison between groups, 13 patients with associated disease were excluded from the group with intense interface hepatitis: 6 patients with kidney transplant, 5 with HIV co-infection and 2 with end-stage renal disease.

In the group of patients with intense interface hepatitis, the subjects were older and the proportions of blood transfusion and abusive alcohol consumption were higher. In addition, these patients presented higher levels of ALT (4.2 vs 1.8, P < 0.001), AST (3.1 vs 1.4, P < 0.001) and GGT (3.8 vs 1.1, P < 0.001). No difference in the proportion of patients with reactive ANA or serum γ-globulin levels was observed between groups (Table 2). (Comparative analysis of general characteristics between groups n (%))

Regarding liver biopsy, the mean number of portal tracts observed was 11. Histological aspects are presented in Table 2. The proportion of patients with moderate to intense lobular necroinflammatory activity and cirrhosis was higher in the group with intense interface hepatitis (P < 0.001).

DISCUSSION

Previous studies have demonstrated that the presence of intense interface hepatitis in patients chronically infected with HCV is rare[19,20]. When this finding is present, other liver diseases, especially autoimmune hepatitis, should be carefully ruled out. In the present study, 1759 patients chronically infected with HCV were initially evaluated and in 92 of them (5.2%) a liver biopsy revealed intense interface hepatitis, indicating that, although uncommon, this finding might be a histological pattern of hepatitis C.

The main objective of the present study was to evaluate the overlap with autoimmune hepatitis in HCV-infected patients with intense interface hepatitis. In this sample only two patients (2%) had serological and histological evidence of autoimmunity in the group with intense interface hepatitis and only one patient had a definitive diagnosis of autoimmune hepatitis based on the International Autoimmune Hepatitis Group scoring system[18]. Although a 12% prevalence of ANA was found among the intense interface hepatitis patients, there was no difference in the proportion of patients with positive ANA when they were compared to patients with less intense necroinflammatory activity. In addition, the prevalence of SMA and anti-LKM was very low in the group with intense interface hepatitis.

No histological lesions typical of autoimmune hepatitis were identified in all except two patients and the proportion of cases presenting a significant plasma cell infiltrate was very low in patients with intense interface hepatitis. The high proportion of patients with rosettes observed in the group with intense interface hepatitis was not considered as suggestive of autoimmune injury, since it reflects hepatic regeneration activity as a consequence of greater necroinflammatory activity and can be observed in other etiologies of liver disease[21,22]. These findings support the suggestion that overlap with autoimmune hepatitis is a very rare association in HCV-infected patients with intense interface hepatitis and raises the possibility that some mechanism related to the host-virus interaction might be responsible for the intense interface hepatitis observed.

Since overlap with autoimmune hepatitis was not found in association with intense necroinflammatory activity in patients with chronic hepatitis C we sought to identify other variables associated with this finding.

In comparison to the control group, the presence of intense interface hepatitis was associated with the following epidemiological characteristics: more advanced age both at the time of infection and at the time of the biopsy, and a higher prevalence of blood transfusion and alcohol abuse. With respect to age at the time of infection, a higher necroinflammatory hepatic activity was observed in patients with more advanced age at HCV infection[19,23]. However, the mechanisms related to this phenomenon are still unknown. One hypothesis is that the ability of the immune system to contain the pathological process triggered by the HCV infection declines with age. It is possible that the higher proportion of patients with a history of blood transfusion in the group with intense interface hepatitis, another association observed in this study, also reflects the association between more advanced age and intense interface hepatitis, since in this sample patients with a history of transfusion were older (P = 0.025).

Excessive alcohol consumption was another variable associated with intense interface hepatitis, suggesting that alcohol may modify the histological injury induced by HCV[23,24], rendering the disease more aggressive even in the absence of lesions characteristic of direct alcoholic hepatic disease. The mechanism whereby alcohol may aggravate the HCV-induced inflammatory process remains obscure.

Analysis of biochemical and histological characteristics demonstrated that patients with intense interface hepatitis present with more severe liver disease, including a high proportion of cirrhosis (63%). With respect to liver enzymes, significantly higher ALT, AST and GGT levels were observed, an expected finding since elevated aminotransferases[25] and GGT[26] levels have been shown to be associated with greater hepatic inflammatory activity.

Although an association between genotype 1 and more intense necroinflammatory activity has been demonstrated[27], no such association between HCV genotype and severity of liver disease was observed in the present study and in most of the studies reported in the literature[28-32].

Regarding histological findings, the histological variables associated with intense interface hepatitis were advanced fibrosis and more intense parenchymatous activity. Although the association between necroinflammatory activity and fibrosis is controversial, this finding supports the hypothesis that necroinflammatory activity influences the progression of hepatic fibrosis as demonstrated in other studies[33-36]. The parenchymatous activity was another variable independently associated with intense interface hepatitis. Although the interface hepatitis is the main histological lesion observed in chronic hepatitis C, whenever the necroinflammatory activity is intense, this process tends to involve all the compartments, and is not restricted to the portal tract.

In conclusion, the absence of elevated γ-globulin levels, the low prevalence of autoantibodies, the occurrence of typical histological findings of autoimmune disease in only two cases (2%), and a definitive diagnosis according to the autoimmune hepatitis score in only one case, suggest that overlap with autoimmune hepatitis is a very rare association in HCV-infected patients with intense interface hepatitis. The uncommon histological presentation of hepatitis C with intense interface hepatitis seems to be related mainly to other host variables.

COMMENTS

Background

Previous studies have demonstrated that intense interface hepatitis is an uncommon finding in chronic hepatitis C. When this finding is present, it raises doubt regarding a possible association with autoimmune hepatitis.

Research frontiers

The main objective of the present study was to evaluate the overlap with autoimmune hepatitis in hepatitis C virus (HCV)-infected patients with intense interface hepatitis.

Innovations and breakthroughs

This study demonstrated that overlap with autoimmune hepatitis is a very rare association in HCV-infected patients with intense interface hepatitis. This finding raises the possibility that some mechanism related to the host-virus interaction might be responsible for this histological pattern.

Applications

Considering that overlap with autoimmune hepatitis in HCV-infected patients with intense interface hepatitis is very uncommon, the best clinical approach for these patients should be antiviral therapy. These results reduce the dilemma of whether immunosuppressive therapy is indicated for patients presenting with this histological finding.

Terminology

Interface hepatitis is a histological finding in liver biopsies observed in chronic hepatitis. It is also termed necroinflammatory periportal activity and was formerly known as piecemeal necrosis. Interface hepatitis is graded as mild, moderate or intense. In this study the authors aimed to evaluate HCV-infected patients with intense interface hepatitis.

Peer review

The paper is well written and represents timely research aimed at identifying a link between hepatitis C and autoimmune hepatitis.

Financial support: Department of Veterans Affairs; Intramural Research Program of the National Institutes of Health (National Institute of Allergy and Infectious Diseases and National Institutes of Health Clinical Center; project Z01 AI000390‐25 and ZIA AI00390‐26 to S.K.).

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services or the Department of Veterans Affairs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.

Abstract

BACKGROUND & AIMS: Multiple viral and host factors are related to the treatment response to pegylated-interferon and ribavirin combination therapy; however, the clinical relevance and relationship of these factors have not yet been fully evaluated. METHODS: We studied 168 patients with chronic hepatitis C who received pegylated-interferon and ribavirin combination therapy. Gene expression profiles in the livers of 91 patients were analyzed using an Affymetrix genechip (Affymetrix, Santa Clara, CA). The expression of interferon-stimulated genes (ISGs) was evaluated in all samples by real-time polymerase chain reaction. Genetic variation in interleukin 28B (IL28B; rs8099917) was determined in 91 patients. RESULTS: Gene expression profiling of the liver differentiated patients into 2 groups: patients with up-regulated ISGs and patients with down-regulated ISGs. A high proportion of patients with no response to treatment was found in the up-regulated ISGs group (P=.002). Multivariate logistic regression analysis showed that ISGs (<3.5) (odds ratio [OR], 16.2; P<.001), fibrosis stage (F1-F2) (OR, 4.18; P=.003), and ISDR mutation (>or=2) (OR, 5.09; P=.003) were strongly associated with the viral response. The IL28B polymorphism of 91 patients showed that 66% were major homozygotes (TT), 30% were heterozygotes (TG), and 4% were minor homozygotes (GG). Interestingly, hepatic ISGs were associated with the IL28B polymorphism (OR, 18.1; P<.001), and its expression was significantly higher in patients with the minor genotype (TG or GG) than in those with the major genotype (TT). CONCLUSIONS: The expression of hepatic ISGs is strongly associated with treatment response and genetic variation of IL28B. The differential role of host and viral factors as predicting factors may also be present. Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Summary. The objective of this study was to find very early viral kinetic markers to predict nonresponse to hepatitis C virus (HCV) therapy in a group of human immunodeficiency virus (HIV)/HCV-coinfected patients. Twenty-six patients (15 HCV genotype-1 and 11 genotype-3) were treated with a 48-week regimen of peginterferon-alfa-2a (PEG-IFN) (180 μg/week) and weight-based ribavirin (11 mg/kg/day). Samples were collected at baseline; 4, 8, 12, 18, 24, 30, 36 and 42 h; days 2, 3, 4, 7, 8, 15, 22, 29, 43 and 57 then weekly and monthly. Five patients discontinued treatment. Seven patients (27%) achieved a sustained virological response (SVR). Nadir HCV RNA levels were observed 1.6 ± 0.3 days after initiation of therapy, followed by a 0.3- to 12.9-fold viral rebound until the administration of the second dose of PEG-IFN, which were not associated with SVR or HCV genotype. A viral decline <1.19 log for genotype-1 and <0.97 log for genotype-3, 2 days after starting therapy, had a negative predictive value (NPV) of 100% for SVR. The day 2 virological response had a similar positive predictive value for SVR as a rapid virological response at week 4. In addition, a second-phase viral decline slope (i.e., measured from day 2 to 29) <0.3 log/week had a NPV = 100% for SVR. We conclude that first-phase viral decline at day 2 and second-phase viral decline slope (<0.3 log/week) are excellent predictors of nonresponse. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of nonresponse in patients with HCV and HIV.

SUMMARY: HIV positive people coinfected with hepatitis C virus (HCV) had an elevated mortality rate compared with the general population in Spain, but this was not the case for individuals with HIV alone, according to a study presented at the XVIII International AIDS Conference (AIDS 2010) last month in Vienna.

By Liz Highleyman

Since the advent of effective combination antiretroviral therapy (ART) in the late 1990s, liver disease has become a growing cause of illness and death among people with HIV. As the proportion of deaths due to AIDS-related opportunistic infections has fallen, the proportion due to liver disease and other non-AIDS conditions has grown. Several studies have found liver disease to be a leading cause of death for HIV positive people in the ART era, though some suggest rates have gone down in recent years.

In part this is because people with HIV are surviving long enough for chronic liver damage -- for example related to viral hepatitis or heavy alcohol use -- to progress to an advanced stage. An estimate one-third of HIV positive people are coinfected with hepatitis B or C. HIV infection itself and antiretroviral drug toxicity may also play a role in liver problems.

In the study presented at AIDS 2010, Santiago Perez-Cachafeiro and colleagues compared liver-related mortality rates in the general population against those of HIV positive patients in 2 Spanish multicenter cohorts, CoRIS-MD (1997-2003) and CoRIS (2004-2008, though follow-up in this analysis extended only through 2006).

The study included 4634 participants, contributing a total of 13,701 person-years of follow-up data. Eligible individuals were HIV positive, ART-naive at study entry, had available HCV test results, and were followed for at least 6 months. Most (about 75%) were men and the median age was 35 years. Nearly 40% had a history of injection drug use and about one-quarter were men who have sex with men; 43% were HIV/HCV coinfected. The median CD4 cell cohort when joining the study was about 270 cells/mm3.

Standardized mortality ratios (SMRs) were estimated by comparing sex- and age- speci?c liver-related mortality rates between the CoRIS cohorts and the Spanish general population as obtained from the National Institute of Statistics from 1997 through 2006.

Results

18 liver-related deaths were reported during the study period.

16 of these deaths were of HIV/HCV coinfected patients, while 2 were HCV negative.

No liver-related deaths occurred between 2004 and the end of data collection in 2006.

The resulting liver-related mortality rate was 0.13 per 100 person-years.

Liver-related SMRs between the cohort participants and general population varied according to patient characteristics.

The liver-related SMR for the overall HIV positive population was 10.0, or 10 times greater risk of death.

People with an AIDS diagnosis had an SMR of 11.2 compared with 9.7 for those who had not progressed to AIDS.

A large difference in increased risk was observed according to hepatitis C status:

--HCV uninfected: SMR 2.0;
--HIV/HCV coinfected: SMR 20.5, or more than 20 times the
risk of liver-related death.

"HIV infected subjects died from liver-related causes 10 times more than the general population but this risk was very different according to HCV co," the investigators concluded. "While HIV monoinfected subjects do not present significant differences compared to the general population, co-infected subjects died 20 times more."

Careers can be made in the drug development business on a single drug like telaprevir, the hepatitis C treatment from Vertex Pharmaceuticals (NASDAQ:VRTX). If it gets approved, the drug has the potential to become a leading treatment for the chronic liver disease—and to make a multibillion-dollar fortune for Cambridge, MA-based Vertex—within the next few years.

So it’s a bit of shocker to people when they find out that the pharmaceutical powerhouse Eli Lilly (NYSE:LLY), which collaborated with Vertex to discover telaprevir, gave away almost its entire stake in the drug back in December 2002. Indianapolis-based Lilly began working with the smaller Vertex to discover drugs for hepatitis C virus in 1997, and telaprevir emerged as the two companies’ lead compound in the program in 2001.

Jump ahead to this spring. Vertex, which has West Coast operations in San Diego, reported in May that telaprevir passed a pivotal test, curing three out of four patients with the disease in a Phase III clinical trial, a major hurdle in its bid to gain FDA approval of the drug. The drug, known as a protease inhibitor, is considered by some a breakthrough because it has shown that it can cure patients at the twice the rate of existing therapies. Company executives say they hope to garner permission to begin sales of the drug in 2011.

While those results have helped Vertex build up a $7 billion market capitalization, hardly anybody remembers who could have been its early collaborator. Lilly played a key part in developing and funding early research of the drug, which analysts now project could become a $2 billion annual seller in the U.S. alone within two years of its potential launch. It’s a decision that Lilly has to regret, given that telaprevir’s potential has made Vertex the third most valuable biotech company based in Massachusetts, behind only Genzyme (NASDAQ:GENZ) and Biogen Idec (NASDAQ:BIIB).

“Telaprevir would not exist if Lilly hadn’t been involved in the collaboration,” says Roger Tung, a founding scientist of Vertex who supervised the group that worked with Lilly researchers on telaprevir. He is now founder and CEO of Lexington, MA-based Concert Pharmaceuticals. “Lilly was very involved, they did a lot of work, and they contributed substantially to the science.”

In hindsight, there’s a lot to be gleaned today from Lilly’s decision to end its work on telaprevir—and Vertex’s moxie to advance the drug into initial clinical trials several years ago on its own and without the backing of a major pharma player. Two former Vertex executives, who were once intimately involved in the firm’s collaboration with Lilly, biotech investor Rich Aldrich and Concert’s Tung, shared their perspectives on the deal that, fortunately for Vertex, fell apart.

At Vertex, the research budget relied heavily on contributions from its large pharma collaborators such as Lilly, GlaxoSmithKline (NYSE:GSK), and Sanofi-Aventis (NYSE:SNY). “We did a lot of deals while I was [at Vertex],” says Aldrich, the former chief business officer of Vertex who led its initial deal with Lilly. “The Lilly deal was an important one.”

During the collaboration, Lilly paid Vertex at least tens of millions of dollars in initial and annual fees and contributed its own scientists’ efforts to advance research of hepatitis C virus. The virus, which causes chronic damage to the liver, affects an estimated 170 million people worldwide and 3 million Americans. Existing drugs for the disease cause flu-like symptoms and patients must typically take them for nearly at year.

However, changes at both Lilly and Vertex led to the two firms’ “mutual decision” to part ways in late 2002. Officially, Lilly wanted out of its partnership with Vertex because of changes in its research priorities, and Vertex wanted to retain greater ownership of the drug than it would have if it kept Lilly as a partner, according to a Vertex regulatory filing.

Unofficially, there was more to the breakup than that. Around the time telaprevir started nearing its first human studies, Lilly tried to renegotiate the original deal it had struck with Aldrich that heavily favored Vertex, according to Tung. Lilly had agreed to pay for clinical development of the drug, tiered royalties to Vertex on potential North American sales of the treatment in the 20-percent range, as well as a portion of funding for Vertex’s planned specialty drug sales force, Aldrich says.

“I assume Lilly’s projections for producing that molecule and running the clinical program got very high as the drug advanced,” says Aldrich, who left Vertex in 2001, the year before the company and Lilly terminated their collaboration. “Add in the projected cost of a big launch in a new area, and the royalty and marketing support built into the deal with Vertex; at some point the projected return-on-investment must have turned negative.”

Tung, who remained at Vertex until 2005, says that unspecified personnel changes at Lilly also factored into the pharma giant’s decision to nix its partnership with Vertex. “Within Lilly, there were personnel issues that led toward this not being one of their more favored programs,” Tung says. “Some of the champions of the program within Lilly eventually got sidelined, so their political ability to push this forward was compromised.” Tung didn’t name who the telaprevir champions were at Lilly, or identify who put the kibosh on the program at Lilly later on.

Eli Lilly did not return a phone call seeking comment on its former partnership with Vertex this week.

In the ultimate pact to end the deal with Lilly, Vertex kept exclusive worldwide rights to telaprevir and Lilly was granted unspecified royalties on potential sales of the drug and others discovered in their collaboration. In the years that followed, Vertex went on to form separate deals to co-develop the drug with Janssen Pharmaceutica, a unit of New Jersey-based health products giant Johnson & Johnson (NYSE:JNJ), and the Japanese drugmaker Mitsubishi Tanabe, for markets outside the United States. Vertex retains exclusive rights to the drug in this country.

Vertex aims to confirm the results of its Phase III study in data from two other late-stage trials, the first of which will be revealed this month and the second in September. As of March 31, the company has spent more than $2.8 billion since its founding in 1989, much of it on the development of telaprevir. So expectations for the drug are quite high.

“Vertex has spent a lot of money to get to this point,” says Aldrich, who still works closely with Tung as co-founder and chairman of Concert. “If telaprevir had failed or just stumbled at any point along they way, they would have been in big trouble. At this point, it looks like the bet will pay off big for Vertex.”

Shame over HIV infection remains great, according to a recent survey by the International Association of Physicians in AIDS Care. The group's president tells us how this stigma is perpetuating the disease.

By Neal Broverman

Among the presentations at July's XVIII International AIDS Conference in Vienna was one by the International Association of Physicians in AIDS Care. IAPAC, headed by president José Zuniga, reported on its AIDS Treatment for Life International Survey (ATLIS), which queried 2,035 HIV-positive people from 12 countries in the Americas, Europe, Asia, and Africa and examined how much shame and discrimination they experience because of their disease as well as the relationships they have with their doctors. Zuniga discussed the survey and its surprising results.

The Advocate: Tell us about ATLIS.

José Zuniga: We identified quite a significant amount of stigma, considering the fact that we’re now well into the 29th year of the HIV epidemic. What was surprising to us was that that stigma is persistent in developed-world settings as well. If we look at the data related to [the admission of] “I feel alone and isolated because I have HIV/AIDS,” the North American data — the only country we surveyed in North America is the United States — was at 42%, which was well above what we expected in Africa, where we had 24%. In addition, there was data indicating that 22% of Americans living with HIV indicated there was no one they could count on to help take care of them, which was quite significant. The other piece we were quite surprised about was that 16% of U.S. respondents cited discrimination due to their sexual orientation.

How was the survey conducted?

From January to March of this year we utilized a variety of media, including Internet and face-to-face interviews. [The methodology] depended on how we could get a nice variety of patients and ensure we reached certain demographics in each country.

So, it sounds like the results were a shock.

Absolutely. Given the fact that a great deal of work has been done around HIV awareness and attempts to address the determinants of stigma through a variety of means, that it persists still was quite troubling.

Something surprising was that a certain percentage of respondents in long-term relationships had not disclosed their HIV status to their spouse or partner. That certainly speaks to the need to advise people living with HIV/AIDS to, by all means, inform their spouses or partners about their serostatus so appropriate prevention methods can be utilized.

Did the respondents say why they were keeping their HIV status from their partners?

There was great fear of disclosure — not just with spouses and partners, but with family members too. That number [of people not disclosing their HIV status to their partners] is at 17% globally, which doesn’t seem that high, but if that continues to increase, we could see significant community and public health implications.

How were the results greeted in Vienna?

Quite surprising, when taken in combination with all the other data we presented. We found in general a significant gap in health care provider–patient communication around a number of issues — that could have a really detrimental effect on people with HIV. For example, we found physicians weren’t counseling their patients on the importance of smoking cessation. A large percentage of people living with HIV/AIDS smoke, larger than the general population. Smoking especially affects people with HIV/AIDS; they’re more at risk for lung cancer and cardiovascular disease. Yet they’re not being counseled on this very issue, and that’s a significant concern because we achieved success through HAART [highly active antiretroviral therapy] but then lose patients as a result of heart attacks and lung cancer.

The other area where we found significant gaps include around the issue of side effects. There are new treatment options that have fewer side effects for patients, but that dialogue is not happening. Which has a direct correlation to adherence; if you’re living with chronic diarrhea as a result of your drugs, you may not be as inclined to adhere to your therapy as much as you should, which could contribute to resistance.

Where do we go from here?

First of all, we need to strengthen our efforts at education in broader society around HIV and its treatment and dispel some notions that continue to exist around individuals who become HIV-positive with respect to the discrimination we found — 16%, and that could obviously be higher, of U.S. respondents say they experience discrimination by their health care providers. We as a professional medical association need to spend more time educating health care providers about the importance of providing a safe place for people with HIV to benefit not just from highly active antiretroviral therapy but a place where they can have primary care services delivered in a nonjudgmental way.

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck today reported that two pivotal Phase III registration studies for boceprevir, its investigational oral hepatitis C protease inhibitor, have been completed and met the primary endpoints: in both studies in patients with chronic hepatitis C virus (HCV) genotype 1 infection, the addition of boceprevir to treatment with PEGINTRON® (peginterferon alfa-2b) and REBETOL® (ribavirin, USP) (Peg/riba) significantly increased the number of patients who achieved sustained virologic response (SVR; defined as undetectable virus levels 24 weeks after the end of treatment), compared to control groups that received Peg/riba plus placebo.

“The response-guided therapy approach used in these studies enabled those patients – both treatment-failure patients and treatment-naïve patients – who had undetectable virus at certain points of the study to achieve SVR with a shorter total treatment duration than current standard therapy”

.Boceprevir, in combination with Peg/riba, is being studied for the treatment of patients with chronic hepatitis C genotype I who have previously been treated (treatment-failure; HCV RESPOND-2) and in patients who are new to treatment (treatment-naïve; HCV SPRINT-2). Abstracts for boceprevir studies have already been submitted for presentation at a medical meeting later this year, and additional abstracts are being submitted this week. Merck plans to submit a New Drug Application (NDA) for boceprevir to the U.S. Food and Drug Administration on a rolling basis, and expects to complete regulatory submissions in the U. S. and E.U. in 2010.

“There is a clear need for new treatment strategies for chronic hepatitis C," said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories. "We look forward to seeking regulatory approvals to bring boceprevir forward to help treat people living with chronic hepatitis C."

The HCV RESPOND-2 and HCV SPRINT-2 studies each evaluated two treatment strategies with boceprevir: 48 weeks of treatment for all patients (4-week lead-in with 1.5 mcg/kg/week of PEGINTRON and an investigational dose of 600-1,400 mg/day of REBETOL, followed by the addition of boceprevir 800 mg three times a day for 44 weeks), and response-guided therapy, in which patients with undetectable virus at week 8 and again at certain points later in the studies were able to stop all treatment at 36 weeks in HCV RESPOND-2 and at 28 weeks in HCV SPRINT-2. Patients who did not meet these criteria continued treatment with Peg/riba alone for a total treatment duration of 48 weeks. Control groups in the studies received Peg/riba at the doses described above plus placebo for 48 weeks.

The HCV RESPOND-2 study was conducted in 403 patients who failed prior therapy at U.S. and international sites, and patients were randomized into the three groups (48 weeks control; 48 weeks control plus boceprevir; control plus boceprevir using response-guided therapy) at a 1:1:1 ratio. In the boceprevir 48-week treatment group, 66 percent of patients achieved SVR, and in the boceprevir response-guided therapy group, 59 percent of patients achieved SVR, compared to 21 percent of patients in the control group (p<0.0001 for both, intent-to-treat analysis).

"These results are very exciting," said Bruce R. Bacon, M.D., professor of internal medicine, Saint Louis University School of Medicine, and co-principal investigator of the HCV RESPOND-2 study. “Patients who failed prior hepatitis C therapy are among the hardest to treat, and the use of boceprevir in this study helped significantly more of these patients achieve undetectable levels of the virus at 24 weeks after the end of therapy than treatment with Peg/riba alone."

In the HCV SPRINT-2 study, 1,097 treatment-naïve patients at U.S. and international sites were enrolled in two separate cohorts, one with 938 non-African-American/Black patients and the other with 159 African-American/Black patients. Patients were randomized into the three treatment groups (48 weeks control; 48 weeks control plus boceprevir; control plus boceprevir using response-guided therapy) at a ratio of 1:2:2. In the study overall, 66 percent of patients in the boceprevir 48-week treatment group achieved SVR, and 63 percent of patients in the response-guided therapy group achieved SVR, compared to 38 percent of patients in the control group (p<0.0001 for both, intent-to-treat analysis).

As specified by the HCV SPRINT-2 study protocol, results for the non-African-American/Black and African-American/Black patient cohorts were analyzed separately. Several previous studies have shown that African-American/Black patients have a lower response to HCV treatment than non-African-American/Black patients.1-3 Among the non-African-American/Black patients in the boceprevir 48-week treatment group, 69 percent achieved SVR, and in the response-guided therapy group, 67 percent of patients achieved SVR, compared to 40 percent in the control group (p<0.0001 for both, intent-to-treat analysis). Among the African-American/Black patients, 53 percent of patients in the 48-week treatment group and 42 percent of patients in the response-guided therapy group achieved SVR, compared to 23 percent in the control group (p=0.004 and p=0.044, respectively, intent-to-treat analysis).

“The response-guided therapy approach used in these studies enabled those patients – both treatment-failure patients and treatment-naïve patients – who had undetectable virus at certain points of the study to achieve SVR with a shorter total treatment duration than current standard therapy,” said Fred Poordad, M.D., chief of hepatology in the division of gastroenterology at Cedars-Sinai Medical Center, associate professor of medicine at the David Geffen School of Medicine, University of California, Los Angeles (UCLA), and co-principal investigator of the HCV SPRINT-2 study.

In the HCV RESPOND-2 study, the five most common treatment-emergent adverse events reported for the boceprevir 48-week treatment group, boceprevir response-guided therapy group and control group, respectively, were: fatigue (57, 54, and 50 percent), headache (40, 43 and 49 percent), nausea (42, 44 and 38 percent), anemia (47, 43 and 20 percent) and dysgeusia (bad taste) (45, 43 and 11 percent). Treatment discontinuations due to anemia were 3 percent and 0 percent for the boceprevir groups, respectively, compared to 0 percent for the control group. Treatment discontinuations due to adverse events overall were 12 percent and 8 percent for the boceprevir groups, respectively, compared to 3 percent for the control group.

In the HCV SPRINT-2 study, the five most common treatment-emergent adverse events reported for the boceprevir 48-week treatment group, boceprevir response-guided therapy group and control group, respectively, were: fatigue (57, 53 and 60 percent), headache (46, 46 and 42 percent), nausea (43, 48 and 42 percent), anemia (49, 49 and 29 percent) and pyrexia (fever) (32, 33 and 33 percent). Treatment discontinuations due to anemia were 2 percent for each of the boceprevir groups compared to 1 percent for the control group. Treatment discontinuations due to adverse events overall were 16 percent and 12 percent for the boceprevir groups, respectively, compared to 16 percent for the control group.

About the studies

The HCV RESPOND-2 study was conducted in patients chronically infected with hepatitis C genotype 1 who failed prior therapy with peginterferon and ribavirin, including those who had experienced prior relapse or who were prior non-responders, and the HCV SPRINT-2 study was conducted in previously untreated (treatment-naïve) patients chronically infected with hepatitis C genotype 1. Approximately 25 percent of patients in each of the studies had less than a 1 log decrease in viral load after the 4-week Peg/riba lead-in period.

Sustained virologic response (SVR), the protocol-specified primary efficacy endpoint, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment in all randomized patients treated with any study medication (Roche TaqMan LLD=9.3 IU/mL). Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient’s 12-week post-treatment assessment was utilized.

In the HCV RESPOND-2 study, patients in the response-guided therapy arm who had undetectable virus at treatment week 8 and week 12 received a total of 36 weeks of therapy (lead-in with Peg/riba followed by the addition of boceprevir for 32 weeks); patients with detectable virus at week 8, but undetectable virus at week 12, stopped boceprevir treatment at week 36 and continued on Peg/riba alone for an additional 12 weeks, for a total treatment duration of 48 weeks. Patients in any arm of the study who had detectable virus at week 12 were considered treatment failures and discontinued treatment.

In the HCV SPRINT-2 study, patients in the response-guided therapy group of the study who had undetectable virus at treatment week 8 through week 24 received a total of 28 weeks of therapy (lead-in with Peg/riba followed by the addition of boceprevir for 24 weeks); patients with detectable virus at week 8, but undetectable virus at week 24, stopped boceprevir treatment at week 28 and continued on Peg/riba alone for a total treatment duration of 48 weeks. Patients in any arm of the study who had detectable virus at week 24 were considered treatment failures and discontinued treatment.

Merck's commitment to advancing hepatitis therapy

Merck is committed to building on its strong legacy in the hepatitis field by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. Extensive research efforts are underway to develop differentiated oral therapies that bring innovation to hepatitis care.

Conference call

Investors are invited to a live webcast of Merck's conference call today at 9:00 a.m. EDT by visiting Merck's Web site, www.merck.com/investors/events-and-presentations/home.html. Institutional investors and analysts can participate in the call by dialing (877) 381-5782 or (706) 758-9927. Journalists are invited to listen in on the call by dialing (800) 399-7917 or (706) 758-9928. A replay of the webcast will be available starting at 11 a.m. EDT today through 5 p.m. EDT on Aug. 11. To listen to the replay, dial (800) 642-1687 or (706) 645-9291. The conference ID No. is 92380347.

About PEGINTRON

PEGINTRON is indicated for use in combination with REBETOL (ribavirin) for the treatment of chronic hepatitis C in patients three years of age and older with compensated liver disease.

The following points should be considered when initiating therapy with PEGINTRON in combination with REBETOL: (1) These indications are based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose. (2) Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection. (3) No safety and efficacy data are available for treatment of longer than one year.

PEGINTRON is also indicated for use alone for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with interferon alpha and who are at least 18 years of age.

The following points should be considered when initiating therapy with PEGINTRON alone: Combination therapy with REBETOL is preferred over PEGINTRON monotherapy unless there are contraindications to, or significant intolerance of, REBETOL. Combination therapy provides substantially better response rates than monotherapy.

NEW YORK, Aug 4 (Reuters) - Merck & Co (MRK.N) said its experimental hepatitis C treatment met the main effectiveness goals of two late-stage studies and it expects to seek approval for the high-profile medicine by the end of the year.

But a much higher percentage of patients taking the Merck drug, compared with those taking standard treatments, dropped out of one of the trials due to adverse events, including anemia.

The drug, boceprevir, was one of the most important experimental products gained by Merck through its acquisition of Schering-Plough Corp last year.

In the two trials, 66 percent of patients who took boceprevir plus standard drugs for a full 48 weeks were cured of the serious liver disease, a significantly higher cure rate than for standard treatment alone. But that compares with a 75 percent cure rate seen in a separate trial of a rival drug being developed by Vertex Pharmaceuticals Inc (VRTX.O).

Boceprevir and Vertex's telaprevir are considered possible blockbuster products because of their potential to cure far more patients and in as little as half the time of standard drugs that require almost a year of treatment and often cause flu-like symptoms that are tough to tolerate.

Vertex shares rose 3.5 percent to $36.47 as investors compared the Merck data with recently released data on the Vertex drug. Merck said it would provide more detailed clinical trial data at a meeting of the American Association for the Study of Liver Diseases that begins Oct. 29 in Boston.

Merck shares rose 19 cents, or 0.5 percent, to $35.01.

The new class of drugs, which are combined with standard treatments, work against the liver-damaging hepatitis C virus by blocking a protein called protease that the virus requires to replicate. The current standard treatments involve a combination of the injectable drug interferon and an anti-viral pill called ribavirin.

"Based on today's top line data, we are maintaining our view that, while telaprevir will likely take a majority of the initial hepatitis C protease inhibitor market, boceprevir will play a role in the category," J.P. Morgan analyst Chris Schott said in a research note.

Schott said investors will get a better picture of the respective strengths and shortcomings of the two drugs when full late-stage trial data on telaprevir and boceprevir are unveiled at the upcoming Boston meeting.

Merck said boceprevir, taken in combination with the company's Pegintron brand of interferon and ribavirin, significantly increased the number of patients who achieved a sustained virologic response, or SVR -- meaning no detectable virus levels 24 weeks after the end of treatment -- compared with those who received the standard drugs plus a placebo.

Achieving SVR, in layman's terms, is considered being cured of the disease.

One of the trials, called HCV RESPOND-2, involved 403 patients with genotype 1, the most common form of hepatitis C, who had failed prior therapy with interferon and ribavirin. The other trial, called HCV SPRINT-2, enrolled 1,097 patients with genotype 1 who had not previously been treated for the virus.

In both trials, a significant number of patients received 48 full weeks of treatment. But patients with undetectable virus at week 8 and again at certain points later in the studies were able to stop all treatment at 36 weeks in the smaller trial, and at 28 weeks in the larger study.

In the HCV RESPOND-2 study, 66 percent of those receiving boceprevir for 48 weeks were cured, while cures were seen in 59 percent of those receiving shorter treatment regimens of the medicine. That compared with a 21 percent cure rate for those receiving standard treatments.

In the HCV SPRINT-2 study of previously untreated patients, 66 percent of those receiving boceprevir for 48 weeks were cured, along with 63 percent of those on shorter regimens. Cures were seen in 38 percent of those receiving standard therapy.

Vertex is expected next month to unveil data from another late-stage trial of telaprevir in tougher-to-treat patients who had failed prior treatment with standard drugs.

Sanford Bernstein analyst Tim Anderson said available data from separate trials of boceprevir and telaprevir suggest the Merck drug is less effective.

Moreover, he said boceprevir seems more likely to cause anemia -- a side effect that could require patients to take intravenous anemia medicines that boost red blood cells. The question is whether the need for an additional anemia drug on top of the three-drug regimen will greatly discourage use of boceprevir, should it be approved.

Anderson forecast boceprevir would garner sales of $330 million in 2015, far below his forecast of $4.3 billion for the Vertex drug. (Reporting by Ransdell Pierson, Lewis Krauskopf and Bill Berkrot, editing by Maureen Bavdek, Dave Zimmerman and John Wallace)

New drugs for hepatitis C and for super-high cholesterol succeeded in late-stage clinical trials and could be on their way to market, the drugs developers announced Wednesday morning.

Merck said that its antiviral drug boceprevir, when added to existing therapy, effectively cured about two-thirds of patients with hepatitis C. That was far better than the cure rate with the existing therapy alone.

Isis Pharmaceuticals and Genzyme said their drug for super-high cholesterol significantly lowered LDL, the so-called “bad cholesterol’’ in patients, who still had very high cholesterol levels despite taking the highest statin doses they could tolerate.

Still, investors had concerns with both drugs. For the cholesterol drug, called mipomersen, some patients had elevated liver enzymes, a sign the drug might damage the liver.

“Efficacy looks good but safety remains a key risk,’’ Geoffrey Meacham, an analyst at J.P. Morgan wrote in a note to clients Wednesday. Shares of Isis, a biotechnology company in Carlsbad, Calif. were down more than 3 percent at about 10 a.m.

Mipomersen, which is injected, is not likely to compete directly with statins like Pfizer’s Lipitor. It is intended initially for a relatively small number of patients with a genetic disorder that leads to extremely high levels of cholesterol.

But the two companies hope to gradually expand it to broader populations, if safety concerns do not stand in the way. Genzyme said it would file for the initial approval from the F.D.A. in the first half of 2011.

Merck is in a heated race with Vertex Pharmaceuticals to bring to market the first of a new class of hepatitis C drugs that are expected to make treatment far more effective and also possibly shorter in duration. The existing treatment — with alpha interferon and ribavirin – can take nearly a year, causes severe side effects and succeeds in eradicating the hepatitis C virus only about half the time.

“This is a compelling profile for boceprevir,’’ Peter S. Kim, president of Merck Research Laboratories, said on a conference call with analysts Wednesday. He said the company would complete its application to the F.D.A. for regulatory approval by the end of this year.

The early read by Wall Street was that Vertex’s drug would not be blown out of the water by boceprevir. Shares of Merck, a huge company, barely budged. Those of Vertex, whose future is heavily dependent on the success of its hepatitis C drug, were up about 5 percent.

Merck, which obtained boceprevir when it acquired Schering-Plough, announced the results of two clinical trials, which were somewhat complicated in their structure.

In a trial involving 1,097 patients who were undergoing treatment for the first time, 66 percent of those who got boceprevir plus standard therapy for 48 weeks had a so-called sustained virologic response, compared to 38 percent of those getting the standard therapy plus a placebo.

In Vertex’s phase 3 trial, the corresponding rates for its drug, telaprevir, were 75 percent and 44 percent.

A sustained virologic response means there was no detectable hepatitis C virus in the patient’s blood 24 weeks after the treatment ended. Many doctors say that is essentially a cure.

Merck’s other trial involved about 400 patients for whom prior treatment had been unsuccessful. For those who got boceprevir in a 48-week treatment regimen, 66 percent had a sustained virologic response, triple the 21 percent for those in the control arm.

Vertex has not yet reported phase 3 results for patients who have failed prior therapy.

Both Merck trials also looked at schemes in which treatment with boceprevir could be stopped at either 28 weeks or 36 weeks if patients had no detectable virus in their blood. The cure rates for those patients was nearly as good as for the full 48-week regimen. Merck did not say, however, how many patients were able to shorten the duration of treatment.

Merck said 15 percent of the patients in the trial testing initial therapy were blacks, a group that has a higher rate of hepatitis C than the rest of the nation’s population and also do less well on the existing therapy.

In the trial 53 percent of the blacks getting the 48-week treatment with boceprevir had a sustained virologic response compared to 23 percent for those in the control group.

The key safety issue for boceprevir appears to be anemia. That is already a side effect of ribarvirin, one of the two drugs now used to treat hepatitis. But the boceprevir seems to make it worse.

Merck executives said that anemia could be controlled using drugs like Procrit or Aranesp.

Both boceprevir and telaprevir inhibit the protease enzyme made by the virus. Both are taken orally three times a day. The patients in both Merck’s and Vertex’s trials had a strain of hepatitis C called genotype 1, which is the most common strain in the United States and Western Europe and is particularly hard to treat.

The aim of this unique research consortium is to grasp the whole organ and its functions in a computer model

In April 2010, an ambitious new project was launched in Germany: The German Virtual Liver Network. Funded by the Federal Ministry of Education and Research (BMBF), this major interdisciplinary research initiative is the only one of its kind in the world that focuses effort on a single organ across multiple scales of complexity. With an allocated budget over five years of approximately 43 million euros, it is also the only research network worldwide to be financed by a single national organization in systems biology. The Network’s goal is to create a computer model of the liver as a complete organ with all of its diverse and essential functions. Thus it should be possible to better understand the processes in the liver and to develop tailor-made medications.

A biochemical factory in the body

The liver is a unique organ: as the central metabolic organ of vertebrates, it synthesizes, converts and breaks down more than 10,000 substances daily, helping the body to digest food and detoxify itself. It aids digestion, controls iron uptake and synthesizes vital proteins such as coagulation factors. Furthermore, hepatic metabolism is a major factor that needs to be considered in drug development, as it is central to toxicity and drug efficacy. The exploration of the liver and its functions by the Network is therefore of the greatest relevance to medicine and the pharmaceutical industry.

Looking to the future with systems biology

In order to get an overall picture both of the liver as a whole and of the diverse and dynamic processes in the organ, the Network’s researchers are looking to systems biology for help. This branch of science, which deals with the exploration of biological processes at the systems level, seeks to create a holistic picture of dynamic life processes at all levels – from the genome to the proteome and up to the complete cell or even an entire organism. In order to achieve this goal, systems biology links quantitative methods from the field of molecular and cellular biology with techniques and tools from the areas of mathematics, computer sciences and systems sciences. “Systems biology can accelerate the transfer from academic research to use on patients and can cut costs in the development of medications. That’s why it is a key technology and a driving force of innovation for individualized medicine of the future,” emphasizes Federal Minister for Education and Research Annette Schavan in a BMBF's press release in July 2010.

From the cell to the whole organ

In recent years, the HepatoSys network dealt intensively with the systems biology of the liver cell. Building on these results, the project’s successor, the German Virtual Liver Network, now aims to understand the processes in cell aggregates up to the entire organ. For this ambitious project spanning the entire nation, 70 research groups from 41 institutions in science and industry have joined forces. Together these scientists aim to develop integrated computer models capable of generating experimentally testable predictions that are relevant to the physiology of the liver, as well as the function of the organism, and how this is disturbed in disease. This will contribute to an improved understanding of the liver as the body’s most important metabolic organ and how its function is affected in disease. By using validated simulations, these models will greatly benefit efforts to find new therapies, to predict how active substances distribute in the organ, where they attack, and how quickly they are broken down. Thus, medications can be developed in a more targeted, efficient and cost-effective manner and tailored to deliver the optimum dosage to the right patient at the right time.

A world leader

The German Virtual Liver Network is the first project worldwide to aim at building a truly multi-scale computer model of a complete organ– from the biomolecular and biochemical processes up to the anatomy of the whole organ – and including them in the simulation. “The challenge is immense, but we are looking forward to accepting it – not only to promote an understanding of the liver, but also to provide a strong impetus to the entire area of systems biological research. Our goal is to give evidence of a genuine impact on healthcare” says Adriano Henney, program director of the German Virtual Liver Network.

Amarillo Biosciences, Inc. (AMAR), a biotech firm focused on using natural human interferon alpha administered in low doses, is targeting diseases similar to those targeted by companies like InterMune, Inc. (ITMN) and Amgen, Inc. (AMGN). Amar is seeking to install a paradigm shift in how interferon is used to treat disease.

Amarillo Biosciences, Inc. (OTC-BB: AMAR) is a biotechnology company focused on using natural human interferon alpha in low doses to target diseases including influenza, hepatitis C and chronic cough in COPD among others.

Amarillo Improves the Age-Old Interferon Therapy

First developed in the early 1980’s, interferon is a protein that is made and released by all nucleotide cells but particularly lymphocytes in response to the presence of pathogens – like viruses, bacteria, or tumor cells. The protein enables communication between cells in order to trigger the immune system to act and eliminate the threat. Currently, three major types of these proteins are being used to combat a number of diseases and disorders, including leukemia.

These same proteins have always existed in the nasal cavity, where it is released in small doses to stimulate the immune system when someone inhales a virus. While traditional interferon usage has focused on higher doses with significant side effects Amarillo Biosciences is focused on using low doses that are without side effects. Moreover, the company’s product is stable at room temperatures, less expensive, and easier to dose without a needle.

Several studies around the world have also confirmed the effectiveness of the treatment. CytoPharm, which licensed the drug in Taiwan and China, isconducting a US FDA and Taiwanese regulatory-approved Phase II trial on 165 hepatitis C patients. The full results aren’t expected until the end of 2010.

Hot and Growing End Markets of Utmost Importance

Amarillo Biosciences is initially focused on three markets, including influenza, hepatitis C and chronic cough (COPD), that represent a combined hundreds of millions of patients and hundreds of millions of dollars in revenues. It is this wide reach that could make the company’s drugs “blockbuster” status and make the company appealing to a variety of possible suitors.

For instance, the importance of effective flu treatments is difficult to overstate after the outbreak in 2008 and 2009. In the US alone, there are an estimated 25-50 million cases of the flu each year, which lead up to 150,000 hospitalizations and 30,000-40,000 deaths annually, according to data from Genentech, Inc. Extrapolated to the worldwide population, the flu is estimated to infect more than a billion people worldwide each year.

Hepatitis C is another condition that affects approximately 3.9 million people in the US and 300 million people worldwide, according to Clinaero, Inc. While the immune system can handle 15% of these cases, the remaining 85% of infected people need to be treated to fully rid of the disease, and many patients can end up having long-term liver infection – otherwise known as chronic hepatitis C – leading sometimes to Cancer.

Finally, chronic cough, or COPD, affects nearly 15 – 20 million US adults and is the fourth leading cause of death in the US. Meanwhile, the World Health Organization estimates that some 2.74 million people die of COPD every year worldwide, making it the 4th leading cause of death next to diseases like HIV/AIDS and coronary heart disease.

Dedication to Unlocking Shareholder Value

Amarillo Biosciences may be diligently working towards development of its revolutionary treatment, but it is also working diligently to maintain and unlock shareholder value. By developing a dietary supplement, MAXISAL(R), to address the market immediately and generate revenues, while negotiating to obtain a commercialization partner willing to pay upfront milestones, the company is hoping to avoid raising debt or equity that it doesn’t need.

Meanwhile, Amarillo’s low-dose oral interferon could represent a significant opportunity for shareholders down the road. With Phase II studies already underway, along with talks with potential partners, this stock could see some significant upside over the near-term.

Merck said Wednesday that between 63% and 66% of hepatitis C patients never treated before achieved a viral cure after receiving the company's experimental drug boceprevir plus the standard of care, according to top-line results from a phase III study known as SPRINT-2.

These boceprevir cure rates were significantly higher than the 38% of hepatitis C patients cured using standard of care alone. On these data, Merck said it will seek approval of boceprevir in the U.S. and Europe by the end of the year.

If approved, boceprevir may have a tough time competing against Vertex's hepatitis C drug telaprevir, which will also be filed for approval later this year. Results from a similar Vertex study in so-called "treatment-naïve" hepatitis C patients released in May showed that telaprevir plus the standard of care achieved a cure rate of 75%.

Moreover, patients can be cured of the hepatitis C virus using Vertex's telaprevir in as little as 24 weeks, while the shortest treatment duration with Merck's boceprevir is 28 weeks.

It's important to note that boceprevir and telaprevir have never been matched head to head in a single study, but that doesn't stop analysts and investors from comparing the efficacy and safety of the two drugs.

"The [boceprevir] data look ok from an efficacy and safety standpoint but we believe that they are inferior to what telaprevir has demonstrated thus far," wrote ISI Group biotech analyst Mark Schoenebaum in an email to clients soon after Wednesday's announcement.

In early trading, Vertex shares were up 5% to $37.04. Merck was essentially flat at $34.85.

Merck Wednesday also released data from a second phase III study known as RESPOND-2 which tested boceprevir in patients who previously failed to respond to treatment with standard of care.

In this study, cure rates for boceprevir patients (who also received standard of care therapy) ranged from 59% to 66%. By comparison, patients who were re-treated with standard of care achieved cure rates of 21%.

NEW YORK, Aug 4 (Reuters) - Merck & Co (MRK.N) said on Wednesday that two late-stage studies of its experimental hepatitis C treatment met their main effectiveness goals, and it expects to seek approval for the high-profile medicine by the end of the year.

But a much higher percentage of patients taking the Merck drug dropped out of one of the trials due to adverse events, including anemia, than those taking standard treatments -- which themselves are known for harsh side effects.

Merck's drug, boceprevir, was one of the most important experimental products gained by Merck through its acquisition of Schering-Plough Corp last year.

It and a similar drug being developed by Vertex Pharmaceuticals Inc (VRTX.O), called telaprevir, have been considered possible blockbuster products because of their potential to cure more patients and in as little as half the time of standard drugs that require almost a year of treatment.

Vertex shares rose almost 6 percent to $37.23, as investors studied the general findings Merck provided. Merck said it would provide detailed clinical trial data at a medical meeting in November. Merck shares were unchanged.

The new class of drugs work against the liver-damaging hepatitis C virus by blocking a protein called protease that the virus requires to replicate. Current treatments, by contrast, involve a combination of the injectable drug interferon and an anti-viral pill called ribavirin.

Merck said boceprevir, taken in combination with the company's Pegintron brand of interferon and ribavirin, significantly increased the number of patients with sustained virologic response -- meaning no detectable virus levels 24 weeks after the end of treatment -- compared with patients receiving Pegintron, ribavirin and a placebo.

One of the trials, called HCV RESPOND-2, involved 403 patients with genotype 1, the most common form of hepatitis C, who had failed prior therapy with interferon and ribavirin. The other trial, called HCV SPRINT-2, enrolled 1,097 patients with genotype 1 who had not previously been treated for the virus.

In both trials, a significant number of patients received 48 full weeks of treatment. But patients with undetectable virus at week 8 and again at certain points later in the studies were able to stop all treatment at 36 weeks in the smaller trial, and at 28 weeks in the larger study. (Reporting by Ransdell Pierson and Lewis Krauskopf, editing by Maureen Bavdek, Dave Zimmerman)

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